The exclusively human bacterial pathogens N. meningitidis and N. gonorrhoeae are capable of colonizing and penetrating the human mucosa, to avoid hosts defenses and to persist in various anatomical niches. In clinical terms, these events may translate into a variety of syndromes ranging from non-symptomatic carriage, to life-threatening bacterial meningitis or pelvic inflammatory disease with tubule scarring. Our aim is to determine the molecular mechanisms that determine the establishment and progression of an infection with the ultimate goal to give direction to the development of new therapeutic strategies and vaccines. The work in this project follows a combined genetic, cell biological and biochemical approach including the genetic manipulation of putative bacterial pathogenicity factors, and the isolation and biochemical purification of relevant bacterial surface antigens and host cell molecules (receptors). In the fiscal year 1999, we published important progress on four (4) fronts: (a) We identified key genes in the assembly of the neisserial pili which directly affected the ability of the microorganisms to adhere to epithelial cells, (b) we discovered a novel mechanism of invasion for Neisseria gonorrhoeae, which may be critically involved for the development of systemic disease (c) we unravelled a molecular mechanism by which gonococci are able to enter epithelial cells that takes advantages of soluble cell matrix components, and (d) we discovered a universal extragenomic mechanism by which bacterial pathogens can expand their pathogenic potential and escape human defense mechanisms. These findings provide important knowledge of mechanisms of bacterial pathogenesis that has relevance well beyond that of the species studied. In addition, our new findings may turn out to be instrumental in the development of new intervention strategies including vaccine development. - Neisseria, pathogenesis, invasion, virulence, genetics, microbial adhesion, receptors